Pharmaceutical compositions and methods employing substituted derivatives of 2-anilinophenylacetic acids and esters

ABSTRACT

PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTITUTED 2-ANILINOPHENYLACETIC ACIDS, THEIR ESTERS AND SALTS HAVE DESIRABLE ABSORPTION PATTERNS FOR PROTECTING THE SKIN AGAINST THE IRRITATING EFFECT OF ULTRAVIOLET LIGHT AND ARE ALSO ANTI-INFLAMMATORYAGENTS. TYPICAL EMBODIMENTS ARE COMPOSITIONS CONTAINING 2-(2,6-DICHLOROANILINO) PHENYLACETIC ACID, THE SODIUM SALT THEREOF AND THE METHYL ESTER THEREOF.

United States Patent (Nice 3,652,762 Patented Mar. 28, 1972 Int. Cl.A61k 27/00 U.S. Cl. 424-60 46 Claims ABSTRACT OF THE DISCLOSUREPharmaceutical compositions containing substituted Z-anilinophenylaceticacids, their esters and salts have desirable absorption patterns forprotecting the skin against the irritating efiect of ultraviolet lightand are also anti-inflammatory agents. Typical embodiments arecompositions containing 2-(2,6-dichloroanilino)phenylacetic acid, thesodium salt thereof and the methyl ester thereof.

CROSS REFERENCE This is a divisional application of Ser. No. 861,571filed Sept. 29, 1969, Ser. No. 861,571 being a continuation-in-part ofthen copending Ser. Nos. 782,206, 782,473 and 625,326 filed Dec. 9,1968, Dec. 9, 1968 and Mar. 23, 1967 respectively, now all abandoned,Ser. No. 782,206 being a continuation-in-part of Ser. No. 625,326 nowabandoned and of Ser. No. 539,826, filed Apr. 4, 1966 and now abandoned.

DETAILED DESCRIPTION The present invention pertains to substituted2-anilinophenylacetic acids, to salts and esters thereof, to methods oftreating inflammatory conditions and of protecting skin againstirritating ultraviolet light, to compositions adapted for these methods,and to novel synthetic methods for the preparation of these compounds.

In a first embodiment, the present invention pertains toZ-(Z-substituted anilino)phenylacetic acids and -acetates of theformula:

c-cooa wherein R is (lower)alkyl, (lower)alkoxy, fluoro or chloro;

each of R and R is hydrogen, (lower)alkyl, chloro or fluoro;

R is hydrogen, (lower)alkyl, (lower)alkoxy, chloro,

fluoro or bromo;

R is hydrogen or (lower) alkyl;

R is hydrogen, (lower)all yl or when R is hydrogen,

benzyl; and R is hydrogen, (lower)alkyl or benzyl.

The Z-(substituted anilino)phenylacetic acids and -acetates of thisfirst embodiment will necessarily have a substituent in the 2-positionof the anilino ring. This su'bstituent, designated by R is a(lower)alkyl, (lower)- alkoxy, chloro or fluoro group, preferably methylor chloro.

In a second embodiment, the present invention pertains to2-(3-trifluoromethylanilino)phenylacetic acids and -acetates of theformula:

5 R R4 I c-cooR 8 R c1 I wherein each of R R R and R is as defined abovefor Formula I (A);

R is hydrogen or trifluoromethyl; and

R is hydrogen or chloro.

In the compounds of Formula I(A) and (B) and in the presentspecification, the term (lower) alkyl means a straight or branchedmonovalent hydrocarbon chain of from 1 to 5 carbon atoms. The term(lower)alkoxy is defined as a (lower)alkyl connected through an etheroxygen link. Thus alkyl includes for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec. butyl, and tert. butyl, preferably methyl orethyl, while (lower)alkoxy includes for example, methoxy, ethoxy,n-propoxy, iso prloploxy, n-butoxy, and isobutoxy, preferably methyl oret y The compounds of Formulas I(=A) and I(B) absorb the irritating raysof ultraviolet light which are primarily responsible for sunburn, thoseof a wavelength of about 290 to about 300-315 millimicrons, while at thesame time they do not absorb the desirable so-called tanning rays ofover 315 millimicrons wavelength. These compounds are, therefore,especially useful as ultraviolet absorbers for cosmetic purposes, e.g.,in sun-tan creams or lotions.

The compounds advantageously also possess anti-inflammatory, analgesicand antipyretic activity combined with a favorable therapeutic index.This activity can be observed in various standard pharmacological tests,as for example in the bolus alba test in rats, the UV-erythema test inguinea pigs, the cotton pellet test in rats, the phenylquinone stretchtest in mice, etc. These properties render the compounds of theinvention additionally suitable for the treatment of rheumatic,arthritic and other inflammatory conditions.

As an example of the anti-inflammatory activity of the compounds, thesodium salt of 2-(2,6-dichloroanilino) phenylacetic acid demonstrates asignificant inhibitory ellect in bolus alba induced edema in the ratpaw, described by G. Wilhelmi, Jap. Journ. Pharmac. 15, (1965).

Topical sun-tan compositions according to the invention contain at leastone compound of Formulas I(A) or I(B) or a pharmaceutically acceptablesalt thereof with a base,

in an amount which absorbs a suflicient amount of ultraviolet radiationhaving a wavelength in the range of from 290 to 315 millimicrons, asWell as a carrier compatible with the compound or salt, the carrierbeing of a creamy to highly fluid consistency so as to provide anointment, cream or oil.

When utilized primarily for their anti-inflammatory activity, thecompounds of the present invention can also be administered orally,rectally or parenterally, in particular intramuscularly. TheZ-(substituted anilino)phenylacetate esters falling under Formulas I(A)and I(B) are principally administered orally or rectally. Suitablepharmaceutical forms include solid and liquid unit oral dosage formssuch as tablets, capsules, powders, suspensions, solutions, syrups andthe like, including sustained release preparations, and fluid injectableforms such as sterile solutions and suspensions. The term dosage form asused in this specification and the claims refer to physically discreteunits to be administered in single or multiple dosage to animals, eachunit containing a predetermined quantity of active material inassociation with the required diluent, carrier or vehicle. The quantityof active material is that calculated to produce the desired therapeuticeffect upon administration of one or more of such units.

Powders are prepared by co-mminuting the compound to a suitably finesize and mixing with a similarly comminuted diluent pharmaceuticalcarrier such as an edible carbohydrate material as for example, starch.Sweetening, flavoring, preservative, dispersing and coloring agents canalso be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. A lubricant such as talc, magnesiumstearate and calcium stearate can be added to the powder mixture as anadjuvant before the filling operation; a glidant such as colloidalsilica may be added to improve flow properties; a disintegrating orsolubilizing agent may be added to improve the avail ability of themedicament when the capsule is ingested.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and disintegrant and pressing into tablets. A powdermixture is prepared by mixing the compound, suitably comrninuted, with adiluent or base such as starch, sucrose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as syrup, starch paste, acacia mucilage or solutions of cellulosicor polymeric materials and forcing through a screen. As an alternativeto granulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosageform so that a given quantity, e.g., a teaspoonful, contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavored aqueous sucrose solutionwhile elixirs are prepared through the use of a non-toxic alcoholicvehicle. Suspensions can be formulated by dispersing the medicament in anon-toxic vehicle in which it is insoluble.

For parenteral administration, fluid unit dosage forms can be preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium. Alternatively a measured amount of the com- 4 poundis placed in a vial and the vial and its contents are sterilized andsealed. An accompanying vial or vehicle can be provided for mixing priorto administration.

The daily dosages, to be taken internally, of compounds of Formulas I(A)or I(B) or pharmaceutically acceptable salts thereof with a base, forthe treatment of rheumatic, arthritic and other inflammatory conditionsis from about 50 to about 1500 mg. for adult patients, although theamounts administered depend upon the species, age and weight of thesubject matter under treatment, as Well as the particular condition tobe treated and the mode of administration. Dosage units such as dragees,tablets or suppositories, preferably contain from about 25 to about 300mg. of a compound of Formulas I(A) or I(B) or a pharmaceuticallyacceptable salt thereof. Unit dosages for oral administration preferablycontain from 1% to of an active ingredient of Formula I(A) or I(B).

Pharmaceutically acceptable salts of the acids falling under FormulasI(A) or I(B) are obtained either in the courses of the production of theacids as described hereafter, or via conventional methods, such as themixing of preferably equimolar amounts of the free acid and the base ina suitable solvent, such as water, methanol, ethanol, diethyl ether,chloroform, methylene chloride or the like. Salts, which in certainsolvents have an appreciably lower solubility than the alkali salts, canalso be produced from the latter by double reaction. Pharmaceuticallyacceptable salts of the acids falling under Formulas I(A) and I(B) aresuch as derived from nontoxic inorganic or organic bases. Examples ofsuch salts are the sodium, potassium, lithium, magnesium, calcium andammonium salts, as well as salts with ethylamine, triethylamine,Z-aminoethanol, 2,2-iminodiethanol, 2-dimethylamino-ethanol,Z-diethylaminoethanol, ethylenediamine, benzylamine, p aminobenzoicacid, 2- diethylamino-ethyl ester, pyrrolidine, piperidine, morpholine,lethyl-piperidine or Z-piperdino-ethanol, and the like. A particularadvantage of the salts is that they tend to stabilize the acids fallingunder Formulas I(A) and I(B).

The compounds of the present invention can be prepared in a number ofways as is more fully described in pending application Ser. No. 861,571,the disclosure of which is hereby incorporated by reference. Thefollowing are typical compounds thus prepared:

Representative of the free acids utilized in the methods andcompositions of the present invention are the followmg:

(a) 2-(2,6-dichloroanilino)phenylacetic acid,

(b) 2-(2-chloro-6-methylanilino) phenylacetic acid,

(c) 2-(2,6-dichloroanilino)-5-chlorophenylacetic acid,

(d) 2- 2,6-dichloro-3-methylanilino -5-chlorophenylacetic acid,

(e) 2- 2,6-dichloro-3-methylanilino -5-methoxyphenylacetic acid,

(f) 2-(2,6-dichloroanilino)-5-methoxyphenylacetic acid,

(g) 2-(2,6-dichloroanilino)-5-bromophenylacetic acid,

(h) 2-(2,6-dichloro-3-methylanilino) phenylacetic acid,

(i) 2-(3-trifluoromethylanilino)phenylacetic acid,

(j) 2-(2-methoxy-5-methylanilino)phenylacetic acid,

(k) 2-(2-chloro-5-trifluoromethylanilino)phenylacetic acid,

(1) 2-(2,3-dimethylanilino) henylacetic acid,

(m) 2-(2-methyl-3-chloroanilino) phenylacetic acid,

(n) 2- [2- (2,6-dichloro-3-methylanilino phenyl] propionic acid,

(0) 2- [2- (2, 6-dichloroanilino phenyl] propionic acid,

(p) 2- 2- (2,6-dichloroanilino -5chlorophenyl] propionic acid,

(q) 2-[2-(2,6-dichloroanilino)phenyl]butyric acid,

(r) 2- [2- 2,6-dichloroanilino phenyl] -3-phenylpropionic acid,

( s) 2- [2- (2,6-dichloroanilino phenyl] -2-n1ethylpropionic acid,

(t) 2-(2,6-dimethylanilino)phenylacetic acid, (u)2-(2,6-dirnethylanilino)-5-methylphenylacetic acid, (v) 2- 3,5-bis(trifiuoromethyl) anilino] phenylacetic acid.

Representative of the salts of the foregoing free acids utilized in themethods and compositions of the present invention are the following:

(a) The sodium salt of 2-(2,6-dichloroanilino)-phenylacetic acid.

(b) The sodium salt of 2-(2,6-dichloroanilino)-5-chlorophenylaceticacid,

(c) The sodium salt of 2-(2,6-dichloro-3-methylanilino) phenylaceticacid,

(d) The sodium salt of 2-[2-(2,6-dichloroanilino)-5-chlorophenyhpropionic acid,

(e) The sodium salt of2-(2-chloro-S-trifluoromethylanilino)-phenylacetic acid,

(f) The potassium salt of 2-(2,6-dichloroanilino)phenylacetic acid,

(g) The sodium salt of 2-(2,6-dimethylanilino)-5-methylphenylaceticacid,

(h) The sodium salt of 2-(2,6-dimethylanilino)phenylacetic acid,

(i) The sodium salt of 2-[3,5-bis(trifluoromethyl)anilinophenyl] aceticacid.

Representative of the esters of the above free acids utilized in themethods and compositions of the present invention are the following:

(a) methyl 2-(2,6-dichloroanilino)phenylacetate, 3

(b) methyl 2-(2,6-dichloroanilino)-5-chlorophenylacetate,

() methyl 2-(2,6-dichloro-3-methylanilino)-5-methoxyphenylacetate,

((1) methyl 2-(3-trifiuoromethylanilino)phenylacetate,

(e) methyl 2-(2-(Z-methoxy-S-methylanilino)phenylacetate (f) methyl2-(2-chloro-S-trifluoromethylanilino)phenylacetate,

(g) methyl 2-[2-(2,6-dichloroanilino)phenyl]propionate, 40

(h) methyl 2- [2- (2,6-di'chloro-3-methylanilino phenyl] propionate,

(i) methyl 2-[2-(2,6-dichloroanilino)phenyl1butyrate,

(j) methyl 2-(2-methyl-3-ch1oroanilino)phenylacetate,

(k) methyl 2-(2,3-dimethylanilino)phenylacetate,

(1) methyl 2-(2,6-dichloro-3-methylanilino)phenylacetate,

(In) ethyl 2-(2,6-dichloroanilino)phenylacetate,

(n) benzyl 2-(2,6-dichloroanilino)phenylacetate,

(0) methyl 2-(2-chloro-6-methylanilino)phenylacetate The followingexamples set forth the manner and process of making typical embodimentsof the invention, without being a limitation thereof, and include thebest mode contemplated by the inventors for carrying out the invention.

Example 1 One kilogram of 2-(2,6-dichloro-3-methylanilino) phenylaceticacid are mixed with 550.0 g. of lactose and 292.0 g. of potato starch,the mixture is moistened with an alcoholic solution of 8.0 g. of gelatinand granulated through a sieve. After drying 60.0 g. of potato starch,60.0 vg. of talcum, 10.0 g. of magnesium stearate and 20.0 g. ofcolloidal silicium dioxide are mixed in and the mixture is pressed into10,000 tablets, each weighing 200 mg. and containing 100 mg. of activesubstance. The tablets can be grooved for better adaption of the dosage.

Example 2 Two hundred grams of2-(2,6-dichloro-3-methylanilino)-phenylacetic acid are well mixed with16 g. of maize starch and 6.0 g. of colloidal silicium dioxide. Themixture is moistened with a solution of 2.0 g. of. stearic acid, 6.0 g.of ethyl cellulose and 6.0 g. of stearin in about 70 ml. of isopropylalcohol and granulated through a sieve III (Ph. Helv. V). The granulateis dried for about 14 hours and then passed through sieve III-Illa. Itis then mixed with 16.0 g. of maize starch, 16.0 g. of talcum and 2.0 g.of magnesium stearate and pressed into 1000 drage cores. These arecoated with a concentrated syrup from 2.000 g. of shellac, 7.500 g. ofgum arabic, 0.150 g. of dyestuff, 2.000 g. of highly dispersed siliciumdioxide, 25.000 g. of talcum and 53.350 g. of sugar and dried. Thedrages obtained each weigh 360 mg. and contain 200 mg. of activesubstance.

Example 3 One kilogram ofmethyl-2-(2,6-dichloro-3-methylanilino)phenylacetate are mixed with550.0 g. of lactose and 292.0 g. of potato starch. The mixture ismoistened with an alcoholic solution of 8.0 g. of gelatin and granulatedthrough a sieve. After drying, 60.0 g. of potato starch, 60.0 g. oftalcum, 10.0 g. of magnesium stearate and 20.0 g. of colloidal silicondioxide are mixed in, and the mixture is pressed into 10,000 tablets,each weighing 200 mg. and containing mg. of active substance. Ifdesired, the tablets can be grooved for better adaption of the dosage.

Example 4 Two hundred grams ofmethyl-2-(2,6-dichloro-3-methylanilino)phenylacetate, 16 g. of maizestarch and 6.0 g. of colloidal silicon dioxide are well mixed. Themixture is moistened with a solution of 2.0 g. of stearic acid, 6.0 g.of ethyl cellulose and 6.0 g. of stearin in about 70 ml. of isopropylalcohol and granulated through a sieve. The granulate is dried for about14 hours and then passed through another sieve. It is then mixed with16.0 g. of maize starch, 16.0 g. of talcum and 2. 0 g. of magnesiumstearate and pressed into 1000 drage cores. These are coated with aconcentrated syrup made from 2.000 g. of shellac, 7.500g. of gum arabic,0.150 g. of dyestulf, 2.000 g. of highly dispersed silicon dioxide,25.000 g. of talcum and 53.350 g. of sugar and dried. The dragesobtained each weigh 360 mg. and contain 200 mg. of active substance.

Dosage units for rectal administration are, for example, suppositorieswhich consist of a combination of a compound of Formula I or a suitablesalt thereof with a neutral fatty foundation, or gelatin rectal capsuleswhich contain a combination of an active substance or a suitable saltthereof with polyethylene glycols (Carbowaxes) of suitable molecularweight.

Ampoules for parenteral, particularly intramuscular, administrationpreferably contain a water soluble salt, e.g., the sodium salt, of asubstituted phenylacetic acid falling under Formula I, in aconcentration of, preferably, 0.5 to 5%, in aqueous solution, optionallytogether with suitable stabilizing agents and buffer substances.

The following prescriptions can be used for the production of sun-tancreams:

Perfume q.s. Water ad 100.0 g.

7 Example 7 G. Methyl2-(2,6-dichloroanilino)phenylacetate 1.0 Parafiinoil (thin liquid) 1.0 Polyoxyethylene-sorbitan monostearate 2.0Polyoxyethylene-sorbitol-lanolin derivative 1.5 Sorbitol solution 70%3.0

Stearic acid 15.0 Preservative and perfume q.s.

Water ad 100.0 g.

Example 8 i G. Ethyl 2-(2,6-chloroanilino)phenylacetate 1.0 Propyleneglycol 28.0 Glycerine monostearate 18.0 Polyoxyethylene-sorbitanmonolaurate 8.0 Thimerosal (solution 1:1000) 1.0

Perfume q.s. Water ad 100.0 g.

Example 9 Twenty grams 2-[3,5 bis(trifluoromethyl)anilino] phenylaceticacid are dissolved in a mixture of 232 ml. of 1 N sodium hydroxidesolution and 500 ml. of boiled water free of pyrogen and the solution ismade up to 2000 ml. with more of the same water. The solution isfiltered, filled into 1000 ampoules of 2 ml. and sterilized. Each 2 ml,ampoule contains 20 mg. of 2-[3,5-bis(trifluoromethyl)anilinoJphenylacetic acid as active ingredient in the formof the sodium salt.

What is claimed is:

1. The method of treating inflammation in a mammal which comprisesadministering thereto an anti-inflammatory effective amount of acompound of the formula:

4 R R l 7 c-cooa nu I ,1

wherein R is (lower)alkyl, (lower)alkoxy, fluoro or chloro;

each of R and R is hydrogen, (lower) alkyl, chloro or fluoro;

R is hydrogen, (lower) alkyl, (lower)alkoxy, chloro,

flnoro or bromo;

R is hydrogen or (lower)alkyl;

R is hydrogen, (lower)alkyl or when R is hydrogen,

benzyl; and

R is hydrogen, (lower)alkyl or benzyl, or

a pharmaceutically acceptable salt thereof when R is hydrogen.

2. The method according to claim 1 where in said compound R is loweralkyl or chloro;

R is hydrogen, (lower)alkyl or chloro;

R is hydrogen, chloro or (lower)alkyl in the 6'-position-,

R is hydrogen or chloro; and

each of R R and R" is hydrogen.

3. The method according to claim 1 where in said compound R is methyl;

R is chloro in the 6'-position; and

each of R R R R R and R is hydrogen.

4. The method according to claim 1 where in said compound R is chloro;

R is methyl;

R is chloro in 6-position; and

8 each of R R R and R" is hydrogen, or the sodium salt thereof. 5. Themethod according to claim 1 where in said compound R is chloro; R ischloro in 6'-position; R is chloro in S-position; and each of R R R andR is hydrogen; or the sodium salt thereof. 6. The method according toclaim 1 where in said compound R is methyl; R is methyl in 6'-position;and each of R R R R and R is hydrogen; or the sodium salt thereof. 7.The method according to claim 1 where in said compound R is methyl; R ismethyl; and each of R R R R and R is hydrogen.

8. The method according to claim 1 where in said compound R is chloro; Ris chloro in 6-position; and each of R R R R and R is hydrogen; or thesodium salt thereof.

9. The method according to claim 1 where in said compound R is methyl; Ris chloro; and each of R R R R and R is hydrogen.

10. The method according to claim 1 where in compound R is (lower)alkylor benzyl.

11. The method according to claim 1 where in compound R is (lower) alkylor chloro; R is hydrogen or (lower)alkyl; R is hydrogen, (lower)alkyl orchloro in 6'-positi0n; R is hydrogen or chloro; each of R and R ishydrogen; and -R is (1owcr)alkyl.

12. The method according to claim 1 Where compound R is methyl; R ischloro in 6'-position; R is methyl; and each of R R R and R is hydrogen.

13. The method according to claim 1 compound R is phloro; R is chloro in6'-position; R is methyl; and each of R R, R and R is hydrogen.

14. The method according to claim 1 compound 'R is chloro; R is methyl;R is chloro in 6'-position; R' is methyl; and each of R R and R ishydrogen.

15. The method according to claim 1 compound R is chloro; R is chloro in6'-position; R is ethyl; and each of R R R and R is hydrogen.

16. The method according to claim 1 compound R is methyl; R is methyl; Ris methyl; and each of R R R and R is hydrogen.

17. The method according to claim 1 compound R is methyl;

said

said

said

said

where where said where said where said tory effective amount of acompound of the formula:

wherein R is hydrogen, (lower)alkyl, (lower)alkoxy, chloro,

fluoro or bromo;

R is hydrogen or (lower) alkyl;

R is hydrogen, (lower)alkyl or when R is hydrogen,

benzyl;

R is hydrogen, (lower)alky1 or benzyl;

R is hydrogen or trifluoromethyl; and

R is hydrogen or chloro, or

a pharmaceutically acceptable salt thereof when R is hydrogen.

20. The method according to claim 19 where in said compound each of R RR R, R and R is hydrogen, or the sodium salt thereof.

21. The method according to claim 19 where in said compound each of R RR R and R is hydrogen and R is chloro, or the sodium salt thereof.

22. The method according to claim 19 where in said compound each of R RR R and R is hydrogen and R is trifluoromethyl, or the sodium saltthereof.

23. The method according to claim 19 where in said compound each of R, RR, R and R is hydrogen and R is methyl, or the sodium salt thereof.

24. The method according to claim 19 where in said compound each of R RR and R is hydrogen, R is methyl and R is chloro.

25. The method of protecting against irritating rays of ultra-violetlight which comprises applying to the skin of a mammal a compound asdefined in claim 19 in an amount suflicient to absorb irritatingultra-violet rays.

26. A pharmaceutical composition comprising (a) an anti-inflammatoryeffective amount of a compound of the formula:

wherein R is (lower)alkyl, lower)alkoxy, fiuoro or chloro; each of R andR is hydrogen, (lower)alkyl, chloro, or fluoro;

R is hydrogen, (lower)alkyl, (lower)alkoxy, chloro,

fluoro or bromo;

R is hydrogen or (lower)alkyl;

R is hydrogen, (lower)alkyl or when R is hydrogen,

benzyl; and R is hydrogen, (lower)alkyl or benzyl, or a pharmaceuticallyacceptable salt thereof when R is hydrogen, and (b) a pharmaceuticallyacceptable carrier. 27. A pharmaceutical composition according to claim26 where in said compound R is (lower)alkyl or chloro; R is hydrogen,(lower)alkyl or chloro; R is hydrogen, chloro or (lower)alkyl in the6'-position R is hydrogen or chloro; and each of R R and R" is hydrogen.

28. A pharmaceutical composition according to claim 26 where in saidcompound R is methyl; R is chloro in the 6'-position; and each of R R RR R and R is hydrogen.

29. A pharmaceutical composition according to claim 26 where in saidcompound R is chloro; R is methyl; R is chloro in 6'-position; and eachof R R R and R is hydrogen, or the sodium salt thereof. 30. Apharmaceutical composition according to claim 26 where in said compoundR is chloro; R is chloro in 6'-position; R is chloro in 5-position; andeach of R R R and R is hydrogen; or the sodium salt thereof. 31. Apharmaceutical composition according to claim 26 where in said compoundR is methyl; R is methyl in 6-position; and each of R R R R and R ishydrogen; or the sodium salt thereof. 32. A pharmaceutical compositionaccording to claim 26 where in said compound R is methyl; R is methyl;and each of R R R R and R is hydrogen.

33. A pharmaceutical composition according to claim 26 where in saidcompound R is chloro; R is chloro in 6-position; and each of R R R R andR is hydrogen; or the sodium salt thereof. 34. A pharmaceuticalcomposition according to claim 26 where in said compound R is methyl; Ris chloro; and each of R R R R and R is hydrogen.

35. A pharmaceutical composition according to claim 26 where in saidcompound R is methyl; R is chloro in 6'-position; R is methyl; and eachof R R, R and R is hydrogen.

36. A pharmaceutical composition according to claim 26 where in saidcompound R is chloro; R is chloro in 6-position; R" is methyl, and eachof R R R and R is hydrogen.

37. A pharmaceutical composition according to claim 26 where in saidcompound R is chloro; R is methyl; R is chloro in 6'-position, R" ismethyl, and each of R R and R is hydrogen.

38. A pharmaceutical composition according to claim 26 where in saidcompound R is chloro;

R is chloro in 6-position; R is ethyl; and each of R R R and R ishydrogen.

39. A pharmaceutical composition according to claim 26 where in saidcompound R is methyl; R is methyl; R is methyl; and each of R R R and Ris hydrogen.

40. A pharmaceutical composition according to claim 26 where in saidcompound R is methyl; R is chloro; R is methyl; and each of R R R and Ris hydrogen.

41. A pharmaceutical composition comprising (a) an anti-inflammatoryeffective amount of a compound of the formula:

wherein R is hydrogen, (lower)alkyl, (lower)alkoxy, chloro,

fluoro or bromo;

R is hydrogen or (lower)alkyl;

12 R is hydrogen, (lower)alkyl or when R is hydrogen,

benzyl; R is hydrogen, (1ower)alkyl or benzyl; R is hydrogen ortrifluoromethyl; and R is hydrogen or chloro, or a pharmaceuticallyacceptable salt thereof when R is hydrogen and (b) a pharmaceuticalcarrier.

42. A pharmaceutical composition according to claim 41 where in saidcompound each of R R R R", R and R is hydrogen, or the sodium saltthereof.

43. A pharmaceutical composition according to claim 41 where in saidcompound each of R R R R and R is hydrogen and R is chloro, or thesodium salt thereof.

44. A pharmaceutical composition according to claim 41 where in saidcompound each of R R R R and R is hydrogen and R is trifluoromethyl, orthe sodium salt thereof.

45. A pharmaceutical composition according to claim 41 where in saidcompound each of R R R, R and R R is hydrogen and R is methyl, or thesodium salt thereof.

46. A pharmaceutical composition according to claim 41 where in saidcompound each of R R R and R is hydrogen, R is methyl and R is chloro.

References Cited UNITED STATES PATENTS 3,413,313 11/1968 Scherrer260--47 STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

am UNITED STATES PATENT OFFICE CASE 2163/61}? H/DIV CERTIFICATE OFCORRECTION Patent No. %,652.Z62 Dated March 28. l 372 Inventor(s) ALFREDSALLMANN ET AL It is certified that error appears in theabove-identified patent that said Letters Patent are hereby corrected asshown below:

and

Column 12, Claim M5, line 19, delete "R and insert R8 line 20, delete"R9".

Signed and sealed this 30th day of January 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents Disclaimer 3,652,762.Alfred Sallmann. Bottmingen, and RudolfPfster. Basel, Switzerland.

PHARMACEUTICAL COMPOSITIONS AND METHODS EM- PLOYING SUBSTITUTEDDERIVATIVES OF Z-ANILINOPI-IE- NYLACETIC ACIDS AND ESTERS. Patent datedMar. 28, 1972. Disclaimer filed Oct. 22, 1984, by the assignee,Ciba-Geigy Corp. Hereby enters this disclaimer to claims 5-7, 9-12,16-19, 22-23, 25-28, 30

32, 34-35, 39-41 and 44-45 of said patent.

[Official Gazette December 18, 1984.]

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE EXTENDING PATENTTERM UNDER 35 U.S.C. 156

Patent No. 3, 652,762

Dated March 28, 1972 Inventor(s) Alfred Sallmann, et al Patent OwnerCiba-Geigy Corporation This is to certify that there has been presentedto the COMMISSIONER OF PATENTS AND TRADEMARKS an application under 35U.S.C. 156 for an extension of the patent term. Since it appears thatthe requirements of the law have been met, this certificate extends theterm of the patent for the period of 2 YEARS with all rights pertainingthereto as provided by 35 USC 156 (b) I have caused the seal of thePatent and Trademark Office to be affixed h day of September 1989.

